Summary Background Radiotherapy is the standard care in elderly patients with malignant astrocytoma and the role of primary chemotherapy is poorly defined. We did a randomised trial to compare the efficacy and safety of dose-dense temozolomide alone versus radiotherapy alone in elderly patients with anaplastic astrocytoma or glioblastoma. Methods Between May 15, 2005, and Nov 2, 2009, we enrolled patients with confirmed anaplastic astrocytoma or glioblastoma, age older than 65 years, and a Karnofsky performance score of 60 or higher. Patients were randomly assigned 100 mg/m 2 temozolomide, given on days 1–7 of 1 week on, 1 week off cycles, or radiotherapy of 60·0 Gy, administered over 6–7 weeks in 30 fractions of 1·8–2·0 Gy. The primary endpoint was overall survival. We assessed non-inferiority with a 25% margin, analysed for all patients who received at least one dose of assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01502241. Findings Of 584 patients screened, we enrolled 412. 373 patients (195 randomly allocated to the temozolomide group and 178 to the radiotherapy group) received at least one dose of treatment and were included in efficacy analyses. Median overall survival was 8·6 months (95% CI 7·3–10·2) in the temozolomide group versus 9·6 months (8·2–10·8) in the radiotherapy group (hazard ratio [HR] 1·09, 95% CI 0·84–1·42, p non-inferiority =0·033). Median event-free survival (EFS) did not differ significantly between the temozolomide and radiotherapy groups (3·3 months [95% CI 3·2–4·1] vs 4·7 [4·2–5·2]; HR 1·15, 95% CI 0·92–1·43, p non-inferiority =0·043). Tumour MGMT promoter methylation was seen in 73 (35%) of 209 patients tested. MGMT promoter methylation was associated with longer overall survival than was unmethylated status (11·9 months [95% CI 9·0 to not reached] vs 8·2 months [7·0–10·0]; HR 0·62, 95% CI 0·42–0·91, p=0·014). EFS was longer in patients with MGMT promoter methylation who received temozolomide than in those who underwent radiotherapy (8·4 months [95e% CI 5·5–11·7] vs 4·6 [4·2–5·0]), whereas the opposite was true for patients with no methylation of the MGMT promoter (3·3 months [3·0–3·5] vs 4·6 months [3·7–6·3]). The most frequent grade 3–4 intervention-related adverse events were neutropenia (16 patients in the temozolomide group vs two in the radiotherapy group), lymphocytopenia (46 vs one), thrombocytopenia (14 vs four), raised liver-enzyme concentrations (30 vs 16), infections (35 vs 23), and thromboembolic events (24 vs eight). Interpretation Temozolomide alone is non-inferior to radiotherapy alone in the treatment of elderly patients with malignant astrocytoma. MGMT promoter methylation seems to be a useful biomarker for outcomes by treatment and could aid decision-making. Funding Merck Sharp & Dohme.

https://www.zora.uzh.ch/id/eprint/64681/1/Sammelmappe7.pdf

Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial

Glioblastoma is the most common malignant primary brain tumor in adults. Its often rapid clinical course, with many medical and psychosocial challenges, requires a multidisciplinary management. Modern multimodality treatment and care improve patients' life expectancy and quality of life. This review covers major aspects of care of glioblastoma patients with a focus on the management of common symptoms and complications. We aim to provide a guide for clinicians confronted with glioblastoma patients in their everyday practice.

Current concepts and management of glioblastoma.

O(6)-methylguanine-DNA-methyltransferase (MGMT) promoter methylation identifies a subpopulation of glioblastoma patients with more favorable prognosis and predicts a benefit from alkylating agent chemotherapy (CT). Little is known about its prevalence and clinical significance in older glioblastoma patients. We studied 233 glioblastoma patients aged 70 years or more (144 males, 89 females, median age: 74 years, range: 70.0-86.6 years), who were prospectively enrolled in the German Glioma Network, for MGMT promoter methylation by methylation-specific PCR (MSP) in all patients and DNA pyrosequencing in 166 patients. MGMT data were correlated with patient outcome. Median progression-free survival (PFS) was 4.8 months (95% CI: 4.3-5.3) and median overall survival (OS) was 7.7 months (95% CI: 6.3-9.0). MGMT promoter methylation was detected by MSP in 134 patients (57.5%). For the whole cohort, PFS was 5.2 versus 4.7 months (p = 0.207) and OS was 8.4 versus 6.4 months (p = 0.031) in patients with versus without MGMT promoter methylation. Patients with MGMT methylated tumors had longer PFS when treated with radiotherapy (RT) plus CT or CT alone compared to patients treated with RT alone. Patients with MGMT unmethylated tumors appeared to derive no survival benefit from CT, regardless of whether given at diagnosis together with RT or as a salvage treatment. Patients treated with RT plus CT or CT alone demonstrated longer OS when pyrosequencing revealed >25% MGMT methylated alleles. Taken together, MGMT promoter methylation may be a useful biomarker to stratify elderly glioblastoma patients for treatment with versus without alkylating agent CT.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.27385

Predictive impact of MGMT promoter methylation in glioblastoma of the elderly

Purpose The management of glioblastoma multiforme (GBM) in elderly patients with poor performance status is not well established A trial evaluating the efficacy and safety of temozolomide alone in this population was undertaken Patients and Methods Patients age 70 years or older with newly diagnosed GBM and postoperative Karnofsky performance score (KPS) less than 70 were eligible for this nonrandomized phase II trial Treatment consisted of 150 to 200 mg/m 2 /d temozolomide for 5 days every 4 weeks until disease progression Radiotherapy was not administered The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), safety, quality of life, and cognition Results Seventy patients (median age, 77 years; median KPS, 60) were enrolled between July 2007 and February 2009 Grade 3 to 4 neutropenia and thrombocytopenia occurred in 13% and 14% of patients, respectively Median PFS was 16 weeks (95% CI, 10 to 20 weeks), and median OS was 25 weeks (95% CI, 19 to 28 weeks), comparing favorably with a 12- to 16-week OS expected from a purely supportive approach Twenty-three patients (33%) improved their KPS by 10 or more points, and 18 (26%) became capable of self-care (KPS 70) Overall quality of life and cognition improved over time before disease progression In the 31 tumors evaluated for O 6 -methylguanine– DNA methyltransferase (MGMT ) promoter methylation, a methylated status indicated longer PFS (26 v 11 weeks; P 03) and OS (31 v 19 weeks; P 03) Conclusion Temozolomide has an acceptable tolerance in elderly patients and GBM and KPS less than 70 It is associated with improvement of functional status in 33% of patients and appears to increase survival compared with supportive care alone, especially in patients with methylated MGMT promoter

Temozolomide in Elderly Patients With Newly Diagnosed Glioblastoma and Poor Performance Status: An ANOCEF Phase II Trial

Background
High grade glioma (HGG) is an aggressive form of brain cancer. Treatment of HGG usually entails biopsy, or resection if safe, followed by radiotherapy. Temozolomide is a novel oral chemotherapy drug that penetrates into the brain and purportedly has a low incidence of adverse events.

Objectives
To assess whether temozolomide has any advantage for treating HGG in either primary or recurrent disease settings.

Search methods
The following databases were searched: CENTRAL (Issue 10, 2012), MEDLINE, EMBASE, Science Citation Index, Physician Data Query and the Meta-Register of Controlled Trials in October, 2012. Reference lists of identified studies were searched. The Journal of Neuro-Oncology and Neuro-oncology were handsearched from 1999 to 2012 including conference abstracts. We contacted neuro-oncologists regarding ongoing and unpublished trials.

Selection criteria
Randomised controlled trials (RCTs) where the interventions were the use of temozolomide during primary therapy or for recurrent disease. Comparisons included no chemotherapy, non-temozolomide chemotherapy or different dosing schedules of temozolomide. Patients included those of all ages with histologically proven HGG.

Data collection and analysis
Two review authors undertook the quality assessment and data extraction. Outcome measures included: overall survival (OS); progression-free survival (PFS); quality of life (QoL); and adverse events.

Main results
For primary therapy three RCTs were identified, enrolling a total of 745 patients, that investigated temozolomide in combination with radiotherapy versus radiotherapy alone for glioblastoma multiforme (GBM). Temozolomide increased OS (hazard ratio (HR) 0.60, 95% confidence interval (CI) 0.46 to 0.79, P value 0.0003) and increased PFS (HR 0.63, 95% CI 0.43 to 0.92, P value 0.02), when compared with radiotherapy alone, although these benefits only appear to emerge when therapy is given in both concomitant and adjuvant phases of treatment. A single RCT found that temozolomide did not have a statistically significant effect on QoL. Risk of haematological complications, fatigue and infections were increased with temozolomide.

In recurrent HGG, two RCTs enrolling 672 patients in total found that temozolomide did not increase OS compared to standard chemotherapy (HR 0.9, 95% CI 0.76 to 1.06, P value 0.2) but it did increase PFS in a subgroup analysis of grade IV GBM tumours (HR 0.68, 95% CI 0.51 to 0.90, P value 0.008). Adverse events were similar between arms.

In the elderly, 2 RCTs of 664 patients found OS and PFS was similar with temozolomide alone versus radiotherapy alone. QoL did not appear to differ between arms in a single trial but certain adverse events were significantly more common with temozolomide.

Authors' conclusions
Temozolomide when given in both concomitant and adjuvant phases is an effective primary therapy in GBM compared to radiotherapy alone. It prolongs survival and delays progression without impacting on QoL but it does increase early adverse events. In recurrent GBM, temozolomide compared with standard chemotherapy improves time-to-progression (TTP) and may have benefits on QoL without increasing adverse events but it does not improve overall. In the elderly, temozolomide alone appears comparable to radiotherapy in terms of OS and PFS but with a higher instance of adverse events.

/pdf/temozolomide-for-high-grade-glioma-55a2un3wko.pdf

Temozolomide for high grade glioma

LBA2002 Background: Despite treatment advances, survival of elderly GBM patients (pts) is usually < 12 months. Hypofractionated RT is advocated in order to shorten treatment time, and chemotherapy has been proposed as an alternative to RT. In a randomized trial we compared two different RT schedules with single-agent TMZ chemotherapy. Methods: Newly diagnosed GBM pts age ≥ 60 years with PS 0-2, were randomized to either standard RT (60 Gy in 2 Gy fractions over 6 weeks) or hypofractionated RT (34 Gy in 3,4 Gy fractions over 2 weeks) or 6 cycles of chemotherapy with TMZ (200 mg/m2 day 1-5 every 28 days). Follow-up including quality of life, symptom checklist, and steroid dosing was completed at 6 weeks, 3 months, and 6 months after start of treatment. The primary study end point was overall survival (OS). Results: A total of 342 pts were included. 291 pts were randomized between the 3 treatment options, 51 pts between hypofractionated RT and TMZ. Median age was 70 years (range 60-88), 59% were male and 72%...

Glioblastoma (GBM) in elderly patients: A randomized phase III trial comparing survival in patients treated with 6-week radiotherapy (RT) versus hypofractionated RT over 2 weeks versus temozolomide single-agent chemotherapy (TMZ).

A. Malmstrom

Papers

Glioblastoma (GBM) in elderly patients: A randomized phase III trial comparing survival in patients treated with 6-week radiotherapy (RT) versus hypofractionated RT over 2 weeks versus temozolomide single-agent chemotherapy (TMZ).